PROJECT SUMMARY A number of serious respiratory diseases cause problems with gas exchange, which is the principal function of the lungs. Some of these are sudden in onset, like lung injury from a severe pneumonia, while others develop over long periods of time, like COPD and Idiopathic Pulmonary Fibrosis (IPF). There is some evidence that the chronic forms of respiratory failure result from loss of the capacity of the lungs to maintain themselves, in part due to dysfunction of resident lung stem cells that normally perform this role. Therefore, discovering the specific molecular and cellular mechanisms by which lung stem cells are regulated throughout life may be helpful for understanding how COPD and IPF develop. Achieving this deep level of understanding about lung stem cell regulation may lead to improved strategies to predict, diagnose, and even pharmacologically treat such diseases. Furthermore, given the easy accessibility of the lung via medical bronchoscopy, it is an ideal organ to target with the delivery of healthy stem cells that might prevent disease progression or even produce improvement if they can be successfully transplanted into diseased lungs. We have found that one of the functional cells in the gas exchange region, the alveolar type II (AT2) cell, acts as a stem cell for mouse lung throughout the lifespan, and identified several factors that regulate its activity. The AIMS of this proposal are to expand our understanding of how these stem cells are regulated by studying the local environment that provides the signals that control their activity, including proliferation and differentiation. We will investigate three specific and distinct aspects of the stem cell behavior, including how it is induced to proliferate to generate new cells, how it attains the capacity to transiently regulate itself in response to injury, and whether the regulatory environment is as or more important than the stem cell itself for maintaining the lungs over the lifespan. Our findings will significantly deepen our understanding of precisely how these lung stem cells can be deliberately manipulated to generate large numbers suitable for cell transplantation, or by pharmacologically driving their activity for therapeutic 're-growth' purposes.